NCGC1481 (NCGC 1481) is a novel potent, type I kinase inhibitor against IRAK1/4 and FLT3, with IC50 of 22.6/0.8 nM and <0.5 nM respectively.
NCGC1481 exhibited potent binding affinity for IRAK1 (Kd=2.9 nM), IRAK4 (Kd=0.3 nM), and FLT3 (Kd=0.3 nM), NCGC1481 demonstrated modest selectivity (>10-fold selectivity versus more than 80% of tested kinases relative to IRAK1, IRAK4, and FLT3) against 369 kinases, inhibited 12/259 kinases with IC50 of <250 nM in the KiNativ in situ kinase profiling platform.
NCGC1481 inhibits compensatory IRAK1/4 signaling and prevents adaptive resistance in FLT3-ITD AML cells in vitro and in vivo, NCGC1481 effectively targets resistant FLT3-ITD AML xenografts.
NCGC1481 targets clinically relevant FLT3-mutant AML cells in vitro.
NCGC1481 is a potent and efficacious small-molecule inhibitor of FLT3-ITD and clinically relevant mutants (D835Y Kd=0.29 nM).
NCGC1481 exhibited superior antileukemic activity against the common, clinically relevant FLT3-mutant AML cells in vitro and in vivo.